nihms630447

Association Between Fatty Acid Supplementation and Prenatal
Stress in African Americans: A Randomized Controlled Trial
Kate Keenan, Ph.D.,
Department of Psychiatry and Behavioral Neuroscience, University of Chicago
Alison E. Hipwell, Ph.D.,
Department of Psychiatry, University of Pittsburgh
Jenna Bortner, B.A.,
Amy Hoffmann, B.A., and
Rose McAloon, B.A.
Abstract
Objective—To test the association between docosahexaenoic acid (DHA)supplementation and
perceived stress and cortisol response to a stressor during pregnancy in a sample of African
American women living in low-income environments.
Methods—Sixty-four African American women were enrolled at 16–21 weeks of gestation.
Power calculations were computed using published standard deviations for the Perceived Stress
Scale and the Trier Social Stress Test. Participants were randomized to either 450 mg per day of
DHA(n=43) or placebo (n=21).At baseline, 24, and 30 weeks of gestation, perceived stress was
assessed by self-report. Cortisol response to a controlled stressor, the Trier Social Stress Test
(TSST) was measured from saliva samples collected upon arrival to the laboratory and after the
completion of the TSST.
Results—Women in the DHA supplementation group reported lower levels of perceived stress at
30 weeks of gestation, controlling for depression and negative life events (mean = 27.4 versus
29.5, (F [3, 47] = 5.06, p = .029, cohen’s d = .65). Women in the DHA supplementation had lower
cortisol output in response to arriving to the laboratory and a more modulated response to the
stressor (F [1.78, 83.85] = 6.24, p = .004, cohen’s d = .76).
Conclusions—Pregnant women living in urban low-income environments who received DHA
reported reduced perceived stress and lower levels of stress hormones in the third trimester. DHA
supplementation may be a method for attenuating the effects of maternal stress during late
pregnancy and improving the uterine environment with regard to fetal exposure to glucocorticoids.
Corresponding author: Kate Keenan, Ph.D., Department of Psychiatry and Behavioral Neuroscience, 5841 South Maryland Avenue,
MC 3077, Room W415, Chicago, IL 60637, 773-702-4449, kekeenan@uchicago.edu.
Financial Disclosure: The authors did not report any potential conflicts of interest.
NIH Public Access
Author Manuscript
Obstet Gynecol. Author manuscript; available in PMC 2015 December 01.
Published in final edited form as:
Obstet Gynecol. 2014 December ; 124(6): 1080–1087. doi:10.1097/AOG.0000000000000559.
NIH-PAAuthorManuscriptNIH-PAAuthorManuscriptNIH-PAAuthorManuscript

Introduction
Consistent with the prenatal programming hypothesis,1 there is now evidence from multiple
studies using a variety of methodologies and across different species that the mother’s level
of psychosocial stress during pregnancy is significantly associated with suboptimal
developmental outcomes in their offspring including disturbances in attention,2–3 impaired
learning and disruption in neurogenesis,4–5 and increased anxiety-like behaviors.2 The
strength of the causal claim is based on rigorous controlled experiments in which the
prenatal effect is distinguished from postnatal effects by using methods such as cross-
fostering or nursery rearing. The pattern of findings in humans closely mirrors those from
controlled animal studies.6–9 The strongest candidate for the mechanism by which prenatal
stress confers risk to the offspring is the maternal hypothalamic-pituitary-adrenal (HPA)
axis,. Prenatal stress causes long-term alterations in the functioning of the offspring’s HPA
axis,10–11 and each of the phenotypic outcomes identified above can be linked with
disruptions in the HPA axis.
A few investigators have examined the effects of DHA supplementation during pregnancy
on later developmental functioning. Neuroprotective effects of DHA supplementation during
pregnancy on the offspring has been reported in controlled animal studies12–14 In humans,
fatty acid supplementation is also associated with reductions in stress reactivity in controlled
studies.15–18 These data converge to support the hypothesis that prenatal DHA
supplementation among women living in stressful environments would lead to reductions in
perceived stress and greater modulation of the activation of the HPA axis in response to
stress.
Materials and Methods
Pregnant women were recruited from Obstetrics Clinics within the University of Pittsburgh
Medical Center from 2010–2012. Sample size was determined based on power calculations
using existing data on perceived stress and cortisol response to the Trier Social Stress Test
(TSST) among pregnant women. Given the goals of the study, only demographically eligible
women were approached for screening. Demographic eligibility included: Medicaid
insurance or Medicaid eligible, African American race, age between 20 and 30 years, and
16–21 weeks of gestation.
In addition to African American women being disproportionately represented among
families living in inner-city poverty in the U.S. and having higher rates of suboptimal birth
outcomes,19 there are race differences in cortisol reactivity to stress and pregnancy.24–26 In
order to control for these group differences either adequate numbers of participants of
different races would need to be included or the study would have to be limited to a single
race. Given the scope of the study, we chose to study African Americans only. We limited
the sample to ages 20–30, which comprises over 60% of pregnancies among African
American.27 This range excluded younger and older ages of mothers during which the risk
for suboptimal pregnancy outcomes increases.
Keenan et al. Page 2

Power calculations were computed using published data: the standard deviation (SD) of
perceived stress using the Perceived Stress Scale was estimated to be 7.4.28 Forty
participants in the supplement group and 20 in the placebo group yielded 80% power to
detect a difference in stress levels of approximately 4 between the two groups using a two-
sided test at the 0.05 significance level. The SD of the cortisol response to the TSST at 20
minutes was estimated to the equal to 8 nmol/L.29 Forty participants in the supplement
group and 20 in the placebo group yielded 80% power to detect a difference in peak
response of approximately 6 nmol/l between the two groups using a two-sided test at the
0.05 significance level.
Women were recruited using two methods. First, research assistants attended obstetric
clinics and provided fliers to patients that listed the demographic inclusion criteria (i.e.,
African American race, Medicaid insurance, gestational age between 16 and 21 weeks, and
maternal age between 20 and 30 years) asking those eligible to complete the screening.
Second, demographically eligible patients identified through electronic medical records
were contacted by mail and phone to assess interest in the study. Telephone screenings were
then conducted to assess eligibility. Exclusion criteria included2 or more servings of sea fish
per week, known medical complications (gestational diabetes, pre-eclampsia, subchorionic
hematoma), regular use of steroid medications, regular alcohol use, cigarettes or use of
illegal substances (by maternal report), use of blood thinners or anti-coagulants, use of
psychotropic medications, BMI >40, and allergy to iodine or soy. One hundred forty-six
participated in screening for eligibility. Of those screened, 26 were ineligible, 64 were
eligible and enrolled, 48 were eligible at time of screening but could not be enrolled prior to
the enrollment window (i.e., 16–21 weeks of gestation), and 8 refused to participate (see
Figure 1).
Participants were reimbursed on an accelerated schedule with $40 for their first visit and an
increase in payments of $10 for each subsequent visit. The Institutional Review Boards of
the University of Chicago and University of Pittsburgh approved all study procedures. This
study also was a registered clinical trial (NCT01158976).
Once enrolled, women were randomly assigned on a 2:1 ratio to receive the omega-3
nutritional supplement (n = 43) or a corn and soybean oil placebo (n = 21) beginning at
enrollment and up through the end of pregnancy. We expected greater variability in the
dependent measures (e.g., stress reactivity) among the experimental participants than the
control patients. Thus, in order to optimize power to test the hypotheses, we enrolled a
higher number of participants in the experimental group to adequately capture that
variability. Women randomized to the study group received the supplement via two gel
capsules providing: 450 mg of DHA; 40 mg of docospentaenoic acid and eicosatetranoic
acid; 90 mg of eicosapentaenoic acid; and 15 IU of vitamin E,, supplied by Nordic Naturals.
Women receiving the placebo received two capsules supplied by Nordic Naturals that were
matched in size, color, and smell to the study drug. The pharmacist at the University of
Pittsburgh used computer generated random assignment of ID numbers to active supplement
or placebo in blocks of nine: six ID numbers were randomized to active supplement and
three to placebo. In order to maintain the double-blind, the pharmacist divided each
randomization block of nine ID numbers into groups of three: three ID numbers were

assigned to group A (placebo) and the remaining six were assigned to either group Bor C,
both of which received identical doses of active supplement. This approach allowed the
pharmacist to randomize on a 2:1 ratio without having the unbalanced design break the
blind. Once the study was complete, the blind was broken and the two groups receiving
identical doses of active supplement were combined for analyses.
Cortisol response to a social evaluative stressor was measured at baseline, 24 and 30 weeks
of gestation. Participants completed questionnaires covering stressful life events, perceived
stress, and symptoms of depression at baseline, 24, and 30 weeks of gestation. Research
assistants contacted participants by phone 3 times per week to ask the time of day that the
supplement was taken, and gathered data on perception of taste, and possible gastrointestinal
side effects to increase compliance.
Symptoms of depression were assessed using the Edinburgh Postnatal Depression Scale,30 a
10-item measure designed to assess pre- and postnatal depression without confounding the
assessment of depression with somatic symptoms of pregnancy (e.g., weight gain, loss of
energy). Internal consistency of in this sample was high: alpha = .88 at baseline; .86 at 24
weeks; .87 at 30 weeks. The Difficult Life Circumstances Scale31 is a set of 28 yes-no
questions about difficult circumstances at home or work that may be a problem for the
primary caregiver. The measure was designed to include items that would be applicable to
women living in poverty such as difficulty with finances and housing. The internal
consistency of the scale as measured by alpha ranged from .73 to .80. The Perceived Stress
Scale32 is a 14-item scale designed to measure the degree to which situations in one’s life
are appraised as stressful. The internal consistency of the scale as measured by alpha was
high: .85 at baseline; .88 at 24 weeks;.87 at 30 weeks.
Following published recommendations for assessing physiological stress reactivity during
pregnancy,33 the Trier Social Stress Test (TSST)34 was used as a psychological stressor. The
TSST procedure consists of a two-minute preparation time, followed by a 5-minute speech
(as if for a job interview), and then a 5-minute mental arithmetic task. The latter two tasks
are performed in front of a video camera and an audience. The TSST typically elicits
individual differences in cortisol reactivity, even during pregnancy.29,35
Saliva was collected at three time points at the baseline, 24 and 30 week assessments: 20
minutes following arrival to the lab, and 20, 45 minutes post-TSST. To collect saliva
samples, an absorbent, unflavored dental roll was applied to the tongue, cheek, and gums for
several minutes. The dental roll was then placed in a labeled plastic salivette. Samples were
immediately transferred to a freezer and stored at −20°C until assayed. On the day of testing,
samples were thawed, centrifuged at 3,000 rpm for 10 minutes allowing for a clear sample to
be pipetted into appropriate test wells. All samples from each subject were assayed in the
same batch to minimize variability, and assayed with reagents from the same lot. Samples
with sufficient saliva were assayed in duplicate using the Salimetrics HS Salivary Cortisol
EIA Kit for unbound cortisol. This assay has a lower limit of sensitivity from .007 to 1.2
µg/dL. The average between-assay variance is 3.9% and 7.1%, and the average within-assay
variance is 6.7% and 6.9% for high and low concentrations, respectively. The correlation
between saliva and serum using the Salimetrics HS Salivary Cortisol EIA Kit and the Coat-

a-Count Serum Cortisol RIA kit is .96, p < .0001. Analyses were conducted with log10-
transformed cortisol values, but are presented as untransformed µg/dL for ease of
interpretation.
Results
Of the 64 participants who completed the baseline assessment, four (6.3%) withdrew from
the study: two participants from each study arm. Two participants randomized to placebo
withdrew due to adverse events: one miscarried and the other withdrew due to mood
changes. Two participants randomized to active supplement withdrew due to adverse events:
one reported headaches and the other upset stomach. Forty-seven participants (73.4%)
attended all three sessions. Descriptive statistics are presented in Table 1 for depression,
negative life events and perceived stress at baseline, 24, and 30 weeks of gestation. Data
collected from all participants, including those who withdrew, are included in the analyses.
Baseline self-report data for one participant in the active group was lost. One participant,
with undetectable cortisol values for five of the nine samples, was not included in the
analyses of cortisol response.
The first goal was to examine group differences in level of depression, negative life events,
and perceived stress by conducting analyses of variance for each measure, controlling for
the other two measures. At baseline and 24 weeks of gestation, there were no group
differences in any of the three measures. At 30 weeks, perceived stress was significantly
lower among the participants receiving supplementation (mean = 27.4) compared to those
receiving placebo (mean = 29.5), controlling for negative life events and depression scores
at 30 weeks (F [3, 47] = 5.06, p = .029, cohen’s d = .65 (Figure 2), a difference of more than
half of a standard deviation for the sample.
Cortisol response to the TSST was examined as a function of group status (supplementation
versus placebo) at baseline, 24 and 30 weeks of gestation by repeated measures analysis of
variance, using a Greenhouse-Geisser correction to account for lack of sphericity. Time of
day was significantly associated with initial cortisol levels at baseline, but not at 24 and 30
weeks; time of day was controlled in analyses involving cortisol levels at baseline.
Cortisol levels before and after the TSST did not vary as a function of supplementation at
baseline or at 24 weeks. At 30 weeks, cortisol levels over time significantly differed as a
function of supplementation (F [1.78, 83.85] = 6.24, p = .004, cohen’s d = .76). As shown in
Figure 3, women who received placebo had higher levels of cortisol upon arrival to the lab
compared to women receiving omega-3 supplementation. Levels for women receiving
placebo were characterized by a relatively steep decline, whereas levels for women
receiving omega-3 supplement evidenced a slight increase in response to the stressor, on
average, followed by decline during the period of recovery. To further probe the differences
in levels upon arrival to the laboratory, the two groups were compared at baseline, 24 weeks,
and 30 weeks of gestation. As shown in Figure 4, cortisol levels upon arrival to the lab were
similar for the two groups at baseline, but diverged over time such that by 30 weeks of
gestation women who received placebo had levels that were on average 20% higher than

women receiving supplement (mean = 0.35 versus 0.27) (F [1.74, 74.63] = 3.51, p = .041,
cohen’s d = .56).
Discussion
The present study was conducted from the perspective of the prenatal programming
hypothesis.1 Specifically, a primary hypothesized mechanism by which prenatal stress
affects offspring development is through exposure of the fetus to high levels of
glucocorticoids released by the mother. This exposure, in turn, affects the fetal stress
architecture in part by adjusting the set point for mounting a stress response and interfering
with the feedback mechanisms for maintaining homeostasis. Although the postpartum
environment continues to affect brain development, it is plausible that this initial insult sets
the stage for a poor developmental trajectory that begins with poorly modulated response to
stress in infancy.
Results from the present study provide preliminary evidence that changes in prenatal
nutrition may be one way to interrupt the suboptimal prenatal programming of the fetus
developing in the context of high levels of maternal stress. Pregnant women living in high
stress, low-income, urban environment who received a fatty acid supplement reported lower
levels of perceived stress than women who received placebo, despite a lack of change in
exposure to stressors. Moreover, the reduction of perceived stress was independent of
depression, which was not associated with fatty acid supplementation. The lack of an
association between DHA supplementation and depression symptoms is consistent with the
literature on perinatal depression. In several randomized controlled trials, DHA was not
associated with depression scores,36–37 but supplementation did appear to enhance the
efficacy of psychopharmacologic treatment for depression,38 suggesting that systems
associated with depressed mood and affect neurotransmission, such as the HPA-axis, are
impacted by fatty acid supplementation.
In fact, evidence from the present study suggests that DHA supplementation does affect the
functioning of the HPA-axis by modulating response to a social stressor. This was
demonstrated primarily via a lower cortisol response to arriving at the laboratory. By 30
weeks of gestation, participants who received DHA supplementation had lower levels of
cortisol upon arrival to the laboratory, and on average demonstrated a slight increase in
cortisol in response to the stressor, a pattern typically observed late in pregnancy.29,33 In
contrast, participants who had received placebo evidenced high levels of cortisol upon
arrival to the laboratory, followed by a steep decrease in cortisol levels during and after
exposure to the TSST. One interpretation of this pattern is that an exaggerated response to
anticipatory stress leads to a less flexible response to the stressor. The high levels of cortisol
upon arrival to the lab followed by a lack of responsiveness to the stressor has been
described as a pattern of dysregulated HPA axis functioning associated with depression both
in adults39 and children.40 Lack of cortisol response to a social stressor also has been
observed among adults reporting high levels of early life adversity, especially females.41
DHA supplementation appears to protect pregnant women living in low-income
environments from manifesting this type of dysregulation.

Demonstrating associations between of fatty acid supplementation and lower prenatal stress,
however, is not sufficient. The next step will be to test the hypothesis that alterations in
maternal stress levels via fatty acid supplementation improves developmental outcomes in
the offspring. Data from other studies support the testing of this hypothesis. For example,
Bolten and colleagues35 reported that cortisol reactivity to the TSST at 32–34 weeks of
gestation, but not basal cortisol levels, was associated with infant self-regulation. Similarly,
Werner and colleagues42 found that infants of women with high levels of maternal cortisol
25 minutes after arrival to the lab during late gestation were more likely to be classified as
“high reactive”(i.e. more motor activity and crying) in response to novel stimuli.
Thus, several important links among prenatal stress, cortisol levels, and infant
neurodevelopment have been demonstrated. Data from our preliminary study are compelling
in terms of the potential impact on health disparities in maternal and infant health, a
significant public health problem that is poorly understood. The findings, however, are in
need of replication. In addition, a number of limitations should be noted. First, the small
sample size and attrition of participants over time likely impact the reliability of the
findings, and thus replication and timing of effects need to be explored in a larger study
population. Although retention across study visits was comparable for the two groups, there
may have been some differential selection bias across the two groups. Second, given the
preliminary nature of the study, we did not control for multiple testing, and of the 13 tests of
significance, we could expect that one may be due to chance. The effect sizes for the
significant results were medium to large, however, providing some indication that the results
are not spurious. Third, we relied on maternal report of uptake as opposed to a rigorous
assessment of blood levels of fatty acids across pregnancy. In addition to the possibility that
uptake varied, blood levels may have varied among individuals with the same level of
supplementation due to other dietary factorsor individual differences in metabolism. Fourth,
although we did not re-administer the TSST after 30 weeks, it would be important to
examine whether differences in cortisol levels as a function of supplementation are
maintained. Moreover, in the context of improving infant outcomes, it may be important to
supplement earlier in gestation. The third trimester is a period of fetal development that may
be particularly sensitive to prenatal stress given the increase in maternal cortisol and
decrease in placental 11β-HSD2, yet exposure earlier in gestation may also confer risk.43
In conclusion, the results reported here extend earlier work on the association between fatty
acid supplementation and improved obstetric outcomes, and complement existing research
on prenatal stress and offspring neurodevelopment by providing preliminary evidence for
nutritional moderation of prenatal stress.
Acknowledgments
Supported by National Institutes of Health grant R21 HD058269 to Dr. Keenan and by the University of Chicago
Institute for Translational Medicine (UL1 TR000430). Nordic Naturals provided the nutritional supplement and
placebo.
The authors thank Joelle Tighe and Suzanne Pierce for their assistance in recruitment and data collection, Kristen
Wroblewski for statistical consultation, and pharmacist Ray Cefola, who conducted the randomization.

Abbreviations
DHA docosahexaenoic acid
TSST Trier Social Stress Test
HPA-Axis hypothalamic pituitary adrenal axis
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an observation-based study. Dev Psychobiol. 2013; 55:707–718. [PubMed: 22778036]
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[PubMed: 20331658]

Figure 1.
Nutrition and Pregnancy Study participation rates. *Eligible at time of screening; but, unable
to schedule baseline within gestational age criterion.

Figure 2.
Effect of omega-3 supplementation on perceived stress score, controlling for negative life
events and depression scores.

Figure 3.
Cortisol levels before and after the Trier Social Stress Test (TSST) at 30 weeks of gestation.
F(1.78, 83.85) =6.24, P=.004; cohen’s d=.76; error bars indicate standard error at each time
point within each group.

Figure 4.
Cortisol levels 20 minutes following arrival to laboratory at baseline, at 24 weeks of
gestation, and at 30 weeks of gestation. F(1.74, 74.63), P=.041; cohen’s d=.56; error bars
indicate standard error at each time point within each group.

Table1
Descriptivestatisticsfordepression,negativelifeevents,andperceivedstressscoresatbaseline,24weeks,and30weeksfortotalsampleandtheactive
andplacebogroups
Baseline24weeks30weeks
Total
N=63
Mean(SD)
Active
N=20
Mean(SD)
Placebo
N=43
Mean(SD)
Total
N=53
Mean(SD)
Active
N=35
Mean(SD)
Placebo
N=18
Mean(SD)
Total
N=51
Mean(SD)
Active
N=34
Mean(SD)
Placebo
N=17
Mean(SD)
Depression12.97(4.9)13.05(5.3)12.80(4.2)12.92(4.8)13.3(5.1)12.11(4.1)11.86(4.9)12.12(4.8)11.35(5.1)
NegativeEvents5.03(3.4)5.16(3.4)4.75(3.6)4.08(3.5)4.57(3.9)3.11(2.4)3.80(0.51)3.91(0.63)3.59(0.89)
Perceivedstress28.16(2.4)27.77(2.2)29.00(2.7)27.94(3.0)28.06(3.5)27.72(2.0)28.08(3.4)27.47(3.4)29.29(3.1)

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